Reinventing Drug Developement

One of the big challenges in front of the chemical community is to reinvent drug development as we know it. A really cool professor at the University of Michigan named Jason Jestwicki published a research paper in 2009 describing one such approach. His stated goal was to stop cytochrome p 450 from metabolizing an HIV protease inhibitor called amprenavir (right). GlaxoSmithKline, the company producing the drug, has dealt with the metabolism problem by distributing the medication in its prodrug form, fosamprenavir (left - note the addition of the phosphate group in the middle of molecule). The prodrug, digested in the body into the active ingredient, increases the absorption and distribution of amprenavir. Professor Jestwicki, instead of adjusting smaller functional groups, looked to nature as inspiration. Tacrolimus, or FK-506 (lower right), was discovered in soil fungus in 1984. FK-506 is a potent immuno suppresant but defies certain expected drug like properties that have been established over the years. For example, it is bigger and has more hydrogen bond donors and acceptors then the majority of FDA approved drugs. After some work, it was shown that FK-506 accumulates in whole blood by binding to a cellular receptor, FKBP. By hiding in the cellular part of whole blood, FK-506 avoids Cytochrome P450 all together. So Professor Jestwicki tethered the FKBP binding functional group to amprenavir (picture available through the pubmed link above) and created a drug that so far has had a half life of 50 hours in vivo as compared to 7-8 hours for fosamprenavir and 80 fold increase in activity.

The critical element to this study is the thought process behind it. Instead of manipulating well developed and understood chemistry that has historically improved bioavalibility, Jestwicki's group utilized a technique from a drug that seemingly has nothing to do with HIV treatment.

Looking over this novel strategy to fight disease I can't help but imagine a place far away where all diseases have their laboratories. A place where graduate students in diabetes and HIV work together to improve resistance to available medication. Where yearly conferences feature cancers and flu viruses on the same panel because they both have figured out a way to utilize genetic variation to survive. We have come to a point in time where we need to look beyond improving target based therapeutics for each particular disease. The method of success inherent to one therapeutic needs to be categorized and applied to as many diseases as possible. The Jestwicki lab identified one such opportunity by connecting HIV medication and an immuno suppressant. We need to have our pro-health graduate students studying cancers and flu talk together and share their methodology for that might be the key for better drug development.

A joke at every end:

A physicist, biologist, and chemist are sitting on the beach and watching the water.
All of a sudden the physicist can't take it anymore and yells "I have to go examine the sine and cosine curves in those waves!" He runs into the water and drowns.
Next the biologist jumps up and yells "I have to go examine the marine life in this ocean!" He runs into the water and drowns.
Finally, the chemists looks up and says "oh look physicists and biologists are water soluble."